The healing of wounds or related forms of tissue damage generally depends on cellular proliferation and the formation of new connective, endothelial, and epithelial tissue. An agent which stimulates or accelerates the cellular processes involved in wound healing would have great value in medical practice and could be used to improve or speed the healing of many types of wounds or lesions, including surgical incisions, burns induced by heat, chemicals, or irradiation, abrasions, lacerations, amputations, ischemic or decubitus ulcers, lesions or ulcers of the mouth, stomach or intestines, skin graft donor sites, and corneal lesions. Such agents may also be important in improving the acceptance of skin or corneal transplants, and in promoting the repair of damaged cartilage or bone.
Agents which accelerate or improve wound healing would be particularly valuable under physiological conditions in which wound healing is impaired, such as in diabetic patients, or in subjects undergoing cancer chemotherapy (e.g. with adriamycin or cyclophosphamide) or corticosteroid treatment, or in patients after therapeutic or accidental exposure to ionizing radiation.
Several agents have been reported to favorably influence the cellular processes involved in wound healing, e.g., polypeptide growth factors, allantoin, Vitamin A (and derivatives), zinc, exogenous DNA, and aloe vera preparations. These compounds operate through various poorly defined mechanisms and display varying degrees of effectiveness in particular applications.
Deoxyribonucleic acid (DNA) has been used to accelerate wound cicatrization or healing. Dumont, Ann. Surg. 150:799 (1959) discloses that exogenous DNA applied to experimental wounds in rabbit ears, accelerated the growth of granulation tissue in the wounds. A mixture of DNA plus deoxyribonuclease (the enzyme primarily responsible for degradation of DNA) was more effective in accelerating fibroplasia than either DNA or deoxyribonuclease alone. The total amount of granulation tissue formed after treatment with DNA was not greater than in untreated controls; the onset and rate of its growth were, however, significantly accelerated. The authors suggest that low polymer DNA fragments are the actual active agents.
Nicolau and Badanoiu, Der Hautartzt, 17:512 (1966) treated experimental skin wounds on the backs of rats daily with intralesion injection of a 1% solution of DNA in physiological saline. The wounds treated with local injection of DNA were cicatrized within four to eight days, while those treated with only saline were cicatrized after ten to fifteen days. A 2% solution of DNA similarly injected into the wounds caused tissue necrosis.
Marshak and Walker, Proc. Soc. Exp. Biol. Med. 58:62 (1945) applied DNA to experimental skin wounds in rats and found significant acceleration of the growth of granulation tissue within the wounds, as compared to untreated controls. Although the granulation tissue appeared sooner in treated wounds, the final amount of granulation tissue was no greater than in untreated wounds.
Ranson (U.S. Pat. No. 4,560,678) discloses a topical formulation containing DNA and allantoin that was used to treat leg ulcers of venous origin. Flecchia (French Patent 2,556,727) discloses a composition containing DNA and bacteriocidal quaternary ammonium compounds for treatment of wounds. U.S. Pat. No. 4,657,896 discloses the use of DNA for treatment of digestive ulcer symptoms particularly when administered parenterally. While local administration of DNA may be effective in promoting wound healing, there are several significant disadvantages to utilization of DNA per se in pharmaceutical preparations which may limit its clinical utility or acceptance. DNA, being extracted from animal tissues, contains other biological materials, e.g., histones or other proteins, which may be antigenic. It is difficult to remove these other biological materials, and, accordingly, commercial high purity DNA is typically about 0.5% protein. In addition, DNA from natural sources may not be uniform from batch to batch. DNA may also have undesirable biological activity beyond its role as a wound healing agent. For example, double-stranded nucleic acids induce interferon formation, probably through interaction with undefined sites on the surface of fibroblasts or lymphocytes. Such effects may not be beneficial and may even be detrimental to wound healing or other biological processes.
DNA also contains phosphate (equimolar to the content of nucleosides) and topical application to wounds may result in high local concentrations of phosphate as the DNA is metabolized. This may be detrimental to the wound healing process and may account for the tissue necrosis that was observed after administration of 2% DNA in the studies of Nicolau et al. Lastly, exogenous DNA can be incorporated into cellular DNA and thereby introduce exogenous functional genes into cells. This is clearly undesirable, particularly if the introduced DNA sequence is that of a virus or oncogene.
U.K. Patent Application No. 2,152,814A to Ogoshi relates to compositions for nutritional replenishment which contain at least two nucleic acid compounds selected from: (a) nucleic acid bases, (b) nucleosides, and (c) nucleotides or salts thereof. The compositions which may be administered parenterally or enterally are said to be capable of enhancing the efficient use of amino acids in the body and of assuring satisfactory nutrition control and maintenance of nitrogen balance.
Japanese Patent No. 60028929 discloses the use of orally administered deoxyguanosine for preventing the formation of stress-induced gastric ulcers in rats. No data were provided concerning the effect (if any) of deoxyguanosine on the healing of gastric ulcers.
U.S. Pat. No. 4,208,406, Lapinet, discloses the use of cyclic 3',5'-adenosine monophosphate (cyclic AMP) as a topical antiinflammatory and healing agent.
While the strategy of delivering healing agents which include inter alia DNA to wounds to accelerate wound healing has been recognized, there remains a need for more effective compositions for the healing of wounds, burns, and other lesions which do not cause undesirable side effects.